Cardiovascular disease is the number one killer of American women. Premenopausal women have a lower incidence of coronary artery disease relative to men;however;after menopause the risk is equal to that of men. Estrogen replacement therapy is effective in relieving the symptoms of menopause but recent clinical trials have failed to demonstrate a significant cardioprotective effect. Therefore, fresh approaches to the concept of "hormone replacement therapy" in postmenopausal women would be useful. We suggest that the ovarian hormone relaxin which circulates during the luteal phase of the menstrual cycle may contribute to the reduced incidence of coronary artery disease in premenopausal women. Although relaxin has been primarily studied as a reproductive hormone, there is growing evidence that relaxin is a potent vasodilator and modifier of arterial compliance which would may make it beneficial for the maintaining coronary artery health. We have recently discovered that relaxin is a vascular derived, locally acting relaxing and compliance factor. Relaxin promotes the health of arteries by making them less contractile and decreasing arterial 'stiffness'. Therefore, we further propose that deficiency of vascular-derived relaxin or its receptor contributes to the increased incidence of cardiovascular disease with aging in women. In hypothesis 1, we will test whether relaxin reverses coronary arterial dysfunction in the post-menopausal rats (ovariectomized Sprague-Dawley rats and aged female SHR, our animal models of menopause). Our preliminary data are exciting, because they support the hypothesis. We will also determine the mechanisms underlying the salutary or health promoting effect of relaxin on coronary artery function. In hypothesis 2, we will test whether reductions in vascular-derived relaxin or its receptor contribute to coronary vascular dysfunction. In summary, premenopausal women have a lower incidence of coronary artery disease that is likely due to the protective effects of female hormones. Ovarian-derived relaxin that circulates during the menstrual cycle or vascular-derived hormone may provide cardiovascular protection prior to menopause. Therefore, relaxin may serve as a "hormone replacement therapy" after menopause. PUBLIC HEALTH RELEVANCE: This proposal outlines studies utilizing isolated rat hearts, isolated coronary arteries, and molecular biology techniques to evaluate the therapeutic potential of relaxin (Rlx) in the treatment of post menopausal coronary artery dysfunction. In addition, we will evaluate the potential contribution of vascular-derived Rlx or its receptor to this coronary artery dysfunction. Two animal models ovariectomized female rats and the aged SHR, will be used to address the aims. Our hope is that these studies may lead to the use of Rlx as an alternative HRT for human coronary artery disease.